Fibrosis is a condition characterized by excess deposition of extracellular matrix components in an organ or tissue that leads to an accumulation of tough fibrous scar tissue. For example, pulmonary fibrosis is a major type of fibrotic disease that is characterized by an inflammatory response that includes macrophages, neutrophils, lymphocytes, and mast cells. Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease with unknown etiology in which normal lung parenchyma is progressively replaced with fibrotic tissue, leading to dyspnea, cough, impaired lung function, and increased mortality. IPF has a poor prognosis, with a median survival of approximately three years from the time of diagnosis, and great associated morbidity, with wide-ranging negative effects on quality of life. Most patients with IPF succumb to respiratory failure. There are several pathogenic events that occur in the development of IPF and several of these events have been targeted by therapeutic agents for the purpose of treating IPF. Therapeutic approaches targeting macrophages, neutrophils or lymphocytes have failed to alter the course of IPF pathogenesis. See Ahluwalia et al., Am J Respir Crit Care Med. 190(8):867-78, 2014 and Woodcock et al., F1000Prime Rep., 6:16, 2014 for a review of IPF and available treatments for IPF. Therefore, there remains a need for therapies that can control the activity of immune cells involved in the pathogenesis of fibrotic disease.
The number of mast cells and mast cell mediators are significantly elevated in IPF. Mast cells are the main source of TGF-β, a cytokine that plays a role in the development of fibrosis via stimulation of collagen production by fibroblasts and signaling for differentiation of fibroblasts into myofibroblasts. It has also been shown that mast cell-deficient mice are protected from bleomycin-induced pulmonary fibrosis. See Veerappan et al., DNA Cell Biol. 32(4):206-18. Although mast cells appear to be involved in the pathogenesis of IPF, their exact role in the multitude of complex pathogenic events that underlay the development of fibrotic disease remains unclear.
Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass transmembrane cell surface proteins found predominantly on leukocytes and are characterized by their specificity for sialic acids attached to cell-surface glycoconjugates. The Siglec family contains at least 15 members that are found in mammals (Pillai et al., Annu Rev Immunol., 30:357-392, 2012). These members include sialoadhesion (Siglec-1), CD22 (Siglec-2), CD33 (Siglec-3), myelin associated glycoprotein (Siglec-4), Siglec-5, OBBP1 (Siglec-6), AIRM1 (Siglec-7), SAF-2 (Siglec-8), and CD329 (Siglec-9). Siglec-8 was first discovered as part of efforts to identify novel human eosinophil proteins. In addition to expression by eosinophils, it is also expressed by mast cells and basophils. Siglec-8 recognizes a sulfated glycan, i.e., 6′-sulfo-sialyl Lewis X or 6′-sulfo-sialyl-N-acetyl-S-lactosamine, and contains an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) domain shown to inhibit mast cell function. Siglec-8 has been shown to modulate cellular responses mediated by the IgE pathway but the effect of Siglec-8 activation on non-IgE mediated immune response pathways is unknown.
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